Medium chain triglyceride compositions

ABSTRACT

A composition comprising medium-chain triglycerides (MCTs) wherein the composition comprises (i) a MCT comprising three fatty acid moieties each with 8 carbon atoms (MCT-C8) and (ii) a MCT comprising three fatty acid moieties each with 10 carbon atoms (MCT-C10); wherein the ratio of MCT-C8 to MCT-C10 is from 10:90 to 90:10 (mol/mol) and wherein the combined amount of MCT-C8 and MCT-C10 make up at least 50 mol % of the MCTs in the composition.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a National Stage of International ApplicationNo. PCT/EP2016/079521, filed on Dec. 2, 2016, which claims priority toEuropean Patent Application No. 15197934.1, filed on Dec. 4, 2015, theentire contents of which are being incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a composition comprising medium chaintriglycerides (MCTs), in particular MCT-C8 and MCT-C10. The presentinvention also relates to the use of the composition for providingketones and/or C10 fatty acids to a subject. The present inventionfurther relates to the use of the composition for the treatment orprevention of conditions associated with brain energy deficiencycondition or disease and neurological conditions.

BACKGROUND TO THE INVENTION

Whilst glucose is understood to be the primary energy source of themammalian brain, impaired glucose metabolism can produce an energydeficit in the brain, and may result in neuronal loss and morphologicalchanges (Hoyer, 1990, Aging (Milano) 2:245-58).

Ketones such as acetone, acetoacetate and β-hydroxybutyrate can serve asan alternative energy source, particularly in periods of prolongedfasting or carbohydrate deficiency. Ketones can be readily used bymitochondria for ATP generation and can be used instead of glucose byneural tissue (Tetrick et al, 2010, Comparative Medicine 60:486-490).Ketones may also exert a protective effect on neurons from free radicaldamage (Vanltallie T B et al, 2003, Ketones: metabolism's ugly duckling.Nutr. Rev. 61:327-41).

Studies have suggested that ketone administration following ischaemicinjury reduces the impact on the brain of the ischaemic injury. Indeed,ketone supplements have been considered as a therapeutic option intraumatic brain injury (White and Venkatesh, 2011, Critical Care15:219). Furthermore, studies suggest that neurodegenerative diseases,such as Parkinson's disease and Alzheimer's disease, will benefit fromketone administration. By way of example, Reger et al, (2004, NeurobiolAging. 25:311-4. 14) found that elevation of serum ketones levels inAlzheimer's patients raised the cognitive scores.

Free fatty acids may be metabolised to ketones and may also serve as analternative source of energy because large quantities of ATP arereleased when fatty acids are metabolized.

Medium-chain triglycerides (MCTs) are medium-chain fatty acid esters ofglycerol. After ingestion of MCTs, the esterified fatty acids arecleaved from the MCT by lipases, such as pancreatic and gastrointestinallipases and the released medium chain fatty acids (MCFA) are transportedas free fatty acids via the portal vein to the liver. MCTs can passivelydiffuse from the gastrointestinal tract to the portal system withoutrequirement for modification like long-chain fatty acids orvery-long-chain fatty acids (You et al, 2008, JPEN 32: 169-175).

MCTs offer a readily available noncarbohydrate fuel source because theyare rapidly absorbed and metabolized into medium-chain fatty acids andketones (Traul et al. Food Chem Toxicol 2000; 38: 79-98). Ketones areactively transported to the brain by, for example, monocarboxylictransporter 1 (MCT1) where they are mainly metabolised by neurones. Freefatty acids, such as C8 free fatty acid and C10 free fatty acid, canalso reach the brain by diffusion where they are mainly metabolised byastrocytes. Thus, medium-chain fatty acids may provide both a direct andan indirect brain fuel source.

Accordingly, free fatty acids and ketones produced from MCTs can providean alternative energy source or a supplementary energy and may be usedto treat a wide range of disorders including neurological disorders andconditions and disorders associated with brain energy deficiency.

SUMMARY OF THE INVENTION

The present inventor has surprisingly found that administering a blendcomprising C8 and C10 MCTs wherein the MCTs are present ashomotriglycerides (i.e. each MCT comprises either three C8 fatty acidsattached to the glycerol backbone or three C10 fatty acids attached tothe glycerol backbone) results in a greater proportion of ketones andfree C10 fatty acids in a bodily fluid (such as plasma) than acorresponding composition wherein a proportion of the MCTs are presentas heterotriglycerides (by heterotriglyceride it is meant that the MCTcomprises a combination of C8 and C10 fatty acids attached to theglycerol backbone such as MCT(mixC8/10 2:1) or MCT(mixC8/10 1:2)).

In particular, the present inventor has surprisingly found that, at thesame overall C8:C10 ratio, a blend comprising homotriglyceride MCTscomprising three fatty acid moieties each with 8 carbon atoms (referredto herein as MCT-C8) and (ii) homotriglyceride MCTs comprising threefatty acid moieties each with 10 carbon atoms (referred to herein asMCT-C10) results in a greater proportion of ketones and C10 free fattyacids in a bodily fluid (such as plasma) than a correspondingcomposition having a mixture of (i) MCT-C8, (ii) MCT-C10, (iii)MCT(mixC8/10 2:1) and (iv) MCT(mixC8/C10 1:2).

Accordingly, in a first aspect of the invention there is provided acomposition comprising MCTs wherein the composition comprises a MCT-C8and a MCT-C10, wherein the ratio of MCT-C8 to MCT-C10 is from 10:90 to90:10 (mol/mol) and wherein the combined amount of MCT-C8 and MCT-C10make up at least 50 mol % of the MCTs in the composition.

Preferably the combined amount of MCT-C8 and MCT-C10 make up at least60, 70, 80, 90, 95, 98, or 99 mol % of the MCTs in the composition.

The ratio of MCT-C8 to MCT-C10 may be 20:80 to 85:15, 20:80 to 80:20,30:70 to 85:15, 40:60 to 75:25, 50:50 to 70:30, 50:50 to 67:33, 55:45 to65:35 or 58:42 to 62:38 (mol/mol).

In one embodiment the ratio of MCT-C8 to MCT-C10 is 58:42 to 62:38(mol/mol).

In another embodiment the ratio of MCT-C8 to MCT-C10 is about 60:40(mol/mol).

In one embodiment the ratio of MCT-C8 to MCT-C10 is 87:13 to 83:17(mol/mol).

In another embodiment the ratio of MCT-C8 to MCT-C10 is about 85:15(mol/mol).

In one embodiment the ratio of MCT-C8 to MCT-C10 is 18:82 to 22:78(mol/mol).

In another embodiment the ratio of MCT-C8 to MCT-C10 is about 20:80(mol/mol).

According to another aspect of the invention there is provided acomposition comprising MCTs wherein the composition comprises a MCT-C8and a MCT-C10, wherein the ratio of MCT-C8 to MCT-C10 is from 50:50 to67:33 (mol/mol). The ratio of MCT-C8 to MCT-C10 may be 55:45 to 65:35 or58:42 to 62:38 (mol/mol).

According to the present invention, MCT-C8 preferably comprises threeoctanoic acid moieties.

That is, the MCT-C8 preferably has the structure:

wherein R1, R2 and R3 are each C₇H₁₅.

According to the present invention, MCT-C10 preferably comprises threedecanoic acid moieties.

That is, the MCT-C10 preferably has the structure:

wherein R1, R2 and R3 are each C₉H₁₇.

In one embodiment at least 50, 60, 70, 80, 90, 95, 98, or 99 mol % ofthe MCTs in the composition are homotriglycerides.

Preferably the composition is free from or substantially free from anyother MCT (i.e. aside from MCT-C8 and MCT-C10).

The composition may be free from or substantially free from any othertriglycerides (i.e. aside from MCT-C8 and MCT-C10).

According to another aspect of the invention there is provided acomposition of the invention for use in providing ketones (e.g.,β-hydroxy butyrate (BHB) and/or aceto acetate (AcA)) and/or C10 fattyacids (e.g., decanoic acid) to a subject. The ketones and/or C10 fattyacids are preferably provided to the subject in a higher concentrationthan when using a corresponding composition wherein a greater proportionof the MCTs are present as heterotriglycerides.

According to another aspect of the invention there is provided acomposition of the invention for use in the treatment or prevention of abrain energy deficiency condition or disease, a neurological condition,migraine, memory disorder, age-related memory disorder, brain injury,stroke, amyloid lateral sclerosis, multiple sclerosis, cognitiveimpairment, cognitive impairment post-intensive care, age-inducedcognition impairment, Alzheimer's disease, Parkinson's disease,Huntingdon's disease, inherited metabolic disorders (such as glucosetransporter type 1 deficiency syndrome and pyruvate dehydrogenasecomplex deficiency), bipolar disorder, schizophrenia, and/or epilepsy.

According to another aspect of the invention there is provided acomposition of the invention for use in providing ketones and/or C10fatty acids to a subject wherein the subject is suffering from a brainenergy deficiency condition or disease, a neurological condition,migraine, memory disorder, age-related memory disorder, brain injury,stroke, amyloid lateral sclerosis, multiple sclerosis, cognitiveimpairment, cognitive impairment post-intensive care, age-inducedcognition impairment, Alzheimer's disease, Parkinson's disease,Huntingdon's disease, inherited metabolic disorders (such as glucosetransporter type 1 deficiency syndrome and pyruvate dehydrogenasecomplex deficiency), bipolar disorder, schizophrenia, and/or epilepsy.

In one embodiment exposure of the subject to ketones and/or C10 fattyacids following oral administration of the composition of the inventionis greater than the exposure following oral administration of acomposition comprising the MCT species shown below:

Mole % MCT-C8 22% MCT-C10 10% MCT(mix C8/C10) 2:1 34% MCT(mix C8/C10)1:2 34%

Preferably the exposure of the subject to ketones and/or C10 fatty acidsfollowing oral administration of the composition of the invention is atleast 2, 3, 4, 5, 6, 7, 8, 9 or 10 mol % greater than following oraladministration of a composition comprising the MCT species shown in theabove table.

Preferably the composition is administered enterally.

In one embodiment the composition may be in the form of a food stuff ora feed.

In an embodiment the composition may be in the form of a medical food, atube feed, a nutritional supplement or a nutritional composition.

In another embodiment the composition may be in the form of a completenutritional product. In another embodiment the composition may providepartial nutrition.

In another embodiment the composition is in the form of a powder,preferably a spray dried powder.

In one embodiment the composition is in the form of an oil-in-wateremulsion.

In another embodiment the composition is in the form of a beverage,mayonnaise, salad dressing, margarine, low fat spread, dairy product,cheese spread, processed cheese, dairy dessert, flavoured milk, cream,fermented milk product, cheese, butter, condensed milk product, icecream mix, soya product, pasteurised liquid egg, bakery product,confectionary product, confectionary bar, chocolate bar, high fat bar,liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding,pasteurised pudding, gel, jelly, yoghurt, or a food with a fat-based orwater-containing filling.

The present invention also provides a method for providing ketonesand/or C10 fatty acids to a subject wherein said method comprisesadministering to the subject a composition of the present invention.

According to another aspect of the present invention there is provided amethod of treating or preventing a brain energy deficiency condition ordisease, a neurological condition, migraine, memory disorder,age-related memory disorder, brain injury, stroke, amyloid lateralsclerosis, multiple sclerosis, cognitive impairment, cognitiveimpairment post-intensive care, age-induced cognition impairment,Alzheimer's disease, Parkinson's disease, Huntingdon's disease,inherited metabolic disorders (such as glucose transporter type 1deficiency syndrome and pyruvate dehydrogenase complex deficiency),bipolar disorder, schizophrenia, and/or epilepsy in a subject whereinsaid method comprising administering to the subject a composition of thepresent invention.

According to another aspect of the present invention there is providedthe use of a composition of the present invention for the manufacture ofa medicament for providing ketones and/or C10 fatty acids to a subject.

According to another aspect of the present invention there is providedthe use of a composition of the present invention for the manufacture ofa medicament for the treatment or prevention of a brain energydeficiency condition or disease, a neurological condition, migraine,memory disorder, age-related memory disorder, brain injury, stroke,amyloid lateral sclerosis, multiple sclerosis, cognitive impairment,cognitive impairment post-intensive care, age-induced cognitionimpairment, Alzheimer's disease, Parkinson's disease, Huntingdon'sdisease, inherited metabolic disorders (such as glucose transporter type1 deficiency syndrome and pyruvate dehydrogenase complex deficiency),bipolar disorder, schizophrenia, and/or epilepsy.

According to another aspect of the present invention there is providedthe use of a composition of the present invention for providing ketonesand/or C10 fatty acids to a subject.

DESCRIPTION OF THE DRAWINGS

FIG. 1—schematic representation of glucose, ketones and free fatty acids(FFA) crossing the blood-brain barrier (BBB). The ketones (β-hydroxybutyrate—BHB) aceto acetate—AcA) and the free fatty acids (C8 FFA andC10 FFA) in this example are derived from MCT plus (MCT+). This Figureshows that MCT can act as a source of energy for the brain.

FIG. 2—rats orally fed a mixture of (i) MCT-C8, (ii) MCT-C10, (iii)MCT-C8 plus MCT-C10 (PLUS) or (iv) MCT(C8/C10MIX) oil (MIX). The levelof C8 free fatty acids, C10 free fatty acids and ketones in the plasmaof rats is shown in Figures (a), (b) and (c) respectively.

FIG. 3—the AUC of C8 free fatty acid and C10 free fatty acid in plasmaover 0 to 24 hours after administration of (i) MCT-C8 plus MCT-C10(PLUS) or (ii) MCT(C8/C10mix) oil (MIX).

DETAILED DESCRIPTION OF THE INVENTION

Medium-Chain Triglyceride (MCT)

A triglyceride (also known as a triacylglycerol or a triacylglyceride)is an ester that is derived from glycerol and three fatty acids.

Fatty acids may be either unsaturated or saturated. Fatty acids whichare not attached to other molecules are referred to as free fatty acids(FFA).

A medium-chain triglyceride (MCT) is a triglyceride in which all threefatty acid moieties are medium-chain fatty acid moieties. As definedherein, medium-chain fatty acids (MCFA) are fatty acids that have 6 to12 carbon atoms. Medium-chain fatty acids with 8 carbon atoms may bereferred to herein as C8 fatty acids or C8. Medium-chain fatty acidswith 10 carbon atoms may be referred to herein as C10 fatty acids orC10.

The term “fatty acid moiety” refers to the part of the MCT thatoriginates from a fatty acid in an esterification reaction withglycerol. In one example, an esterification reaction between glyceroland only octanoic acid would result in a MCT with octanoic acidmoieties. In another example, an esterification reaction betweenglycerol and only decanoic acid would result in a MCT with decanoic acidmoieties.

Octanoic acid (also known as caprylic acid) is a saturated fatty acid ofthe formula CH₃(CH₂)₆COOH.

Decanoic acid (also known as capric acid) is a saturated fatty acid ofthe formula CH₃(CH₂)₈COOH.

The composition of the present invention preferably compriseshomotriglycerides (i.e. all of the fatty acid moieties of the MCT are ofthe same identity, for example a C8 homotriglyceride may comprise 3octanoic acid moieties).

The MCT may be a homotriglyceride comprising three fatty acid moietieseach with 8 carbon atoms; this is referred to herein as MCT-C8.Preferably, all three fatty acid moieties of the MCT-C8 used in thecomposition of the present invention are octanoic acid moieties.

The MCT may be a homotriglyceride comprising three fatty acid moietieseach with 10 carbon atoms; this is referred herein as MCT-C10.Preferably, all three fatty acid moieties of the MCT-C10 used in thecomposition of the present invention are decanoic acid moieties.

An MCT comprising one fatty acid moiety with 8 carbon atoms and whereinthe remaining two fatty acid moieties have 10 carbon atoms is referredto herein as MCT(mixC8/10 1:2).

An MCT comprising two fatty acid moieties with 8 carbon atoms andwherein the remaining fatty acid moiety has 10 carbon atoms is referredto herein as MCT (mixC8/10 2:1).

Examples of natural sources of MCT include plant sources such ascoconuts, coconut oil, palm kernels, palm kernel oils, and animalsources such as milk. Decanoic acid and octanoic acid form about 5-8%and 4-10% of the fatty acid composition of coconut oil, respectively.

MCTs may also be synthesised by esterification of glycerol with one ormore medium-chain fatty acids (MCFA) with a tail of 6 to 12 carbonatoms. For example, MCT-C8 can be synthesised by esterification ofglycerol with C8 fatty acids (e.g. octanoic acid) and MCT-C10 can besynthesised by esterification of glycerol with C10 fatty acids (e.g.decanoic acid).

Composition

There is provided herein a composition comprising medium-chaintriglycerides (MCTs) wherein the composition comprises (i) ahomotriglyceride MCT comprising three fatty acid moieties each with 8carbon atoms (MCT-C8) and (ii) a homotriglyceride MCT comprising threefatty acid moieties each with 10 carbon atoms (MCT-C10).

In one embodiment, the ratio of MCT-C8 to MCT-C10 is from 10:90 to 90:10(mol/mol). In one embodiment, the ratio of MCT-C8 to MCT-C10 is from20:80 to 85:15 (mol/mol). In another embodiment, the ratio of MCT-C8 toMCT-C10 is from 20:80 to 80:20 (mol/mol). In another embodiment, theratio of MCT-C8 to MCT-C10 is from 30:70 to 85:15 (mol/mol). In oneembodiment, the ratio of MCT-C8 to MCT-C10 is from 30:70 to 70:30(mol/mol). In another embodiment the ratio of MCT-C8 to MCT-C10 is about50:50 to about 70:30 (mol/mol). In another embodiment the ratio ofMCT-C8 to MCT-C10 is about 50:50 to about 67:33 (mol/mol). In anotherembodiment the ratio of MCT-C8 to MCT-C10 is about 55:45 to about 65:35(mol/mol). In another embodiment the ratio of MCT-C8 to MCT-C10 is about56:44 to about 62:38 (mol/mol). In one embodiment the ratio of MCT-C8 toMCT-C10 is about 58:42 to about 62:38 (mol/mol). In one embodiment theratio of MCT-C8 to MCT-C10 is about 60:40 (mol/mol).

For example, the ratio of MCT-C8 to MCT-C10 may be about 90:10, about89:11, about 88:12, about 87:13, about 86:14, about 85:15, about 84:16,about 83:17, about 82:18, about 81:19, about 80:20, about 79:21, about78:22, about 77:23, about 76:24, about 75:25, about 74:26, about 73:27,about 72:28, about 71:29, 70:30, about 69:31, about 68:32, about 67:33,about 66:34, about 65:35, about 64:36, about 63:37, about 62:38, about61:39, about 60:40, about 59:41, about 58:42, about 57:43, about 56:44,about 55:45, about 54:46, about 53:47, about 52:48, about 51:49, about50:50, about 49:51, about 48:52, about 47:53, about 46:54, about 45:55,about 44:56, about 43:57, about 42:58, about 41:59, about 40:60, about39:61, about 38:62, about 37:63, about 36:64, about 35:65, about 34:66,about 33:67, about 32:68, about 31:69, about 30:70, about 29:71, about28:72, about 27:73, about 26:74, about 25:75, about 24:76, about 23:77,about 22:78, about 21:79, about 20:80, about 19:81, about 18:82, about17:83, about 16:84, about 15:85, about 14:86, about 13:87, about 12:88,about 11:89 or about 10:90 (mol/mol).

Preferably at least 50, 60, 70, 80, 90, 95, 98, or 99 mol % of the MCTsin the composition are homotriglycerides.

Preferably at least 60, 70, 80, 90, 95%, 98, or 99 mol % of the MCTs inthe composition are MCT-C8 and MCT-C10.

In one embodiment at least 60, 70, 80, 90, 95%, 98, or 99 mol % of thetriglycerides in the composition are MCT-C8 and MCT-C10.

In one embodiment the composition according to the present invention isfree from or substantially free from any other MCT. As used herein, theterm “free from any other MCT” means that the composition does notcomprise any MCT other than MCT-C8 and MCT-C10. As used herein, the term“substantially free from any other MCT” means that the compositioncomprises MCT-C8 and MCT-C10 but there may be traces (e.g., less than 3,2, 1 or 0.5 mol %) of other MCTs.

In one embodiment the composition according to the present invention isfree from or substantially free from any other triglycerides. As usedherein, the term “free from any other triglycerides” means that thecomposition does not comprise any triglycerides other than MCT-C8 andMCT-C10. As used herein, the term “substantially free from any othertriglycerides” means that the composition comprises MCT-C8 and MCT-C10but there may be traces (e.g., less than 5, 3, 2, 1 or 0.5 mol %) ofother triglycerides.

The composition may further comprise substances such as minerals,vitamins, salts, functional additives including, for example, palatants,colorants, emulsifiers, antimicrobial or other preservatives. Mineralsthat may be useful in such compositions include, for example, calcium,phosphorous, potassium, sodium, iron, chloride, boron, copper, zinc,magnesium, manganese, iodine, selenium, chromium, molybdenum, fluorideand the like. Examples of vitamins that may be useful in compositionsdescribed herein include water soluble vitamins (such as thiamin(vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenicacid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7),myo-inositol (vitamin B8) folic acid (vitamin B9), cobalamin (vitaminB12), and vitamin C) and fat soluble vitamins (such as vitamin A,vitamin D, vitamin E, and vitamin K) including salts, esters orderivatives thereof. Inulin, taurine, carnitine, amino acids, enzymes,coenzymes, and the like may be useful to include in various embodiments.

The composition may further comprise one or more agents that promote orsustain general neurologic health or further enhance cognitive function.Examples of such agents include choline, phosphatidylserine,alpha-lipoic acid, CoQ10, acetyl-L-carintine, herbal extracts (such asGingko biloba, Bacopa monniera, Convolvulus pluricaulis and Leucojumaestivum), omega-3 or omega-6 polyunsaturated fatty acids (such aseicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid asfree fatty acid), aliphatic ester (such as ethylester, triglycerides ormonoglycerides formats), and fish oil extracts.

In one embodiment the composition is in the form of a tablet, dragee,capsule, gel cap, powder, granule, solution, emulsion, suspension,coated particle, spray-dried particle or pill.

In another embodiment the composition may be in the form of a powder.The powder may, for example, be a spray-dried powder or a freeze-driedpowder.

The composition may be usable for reconstitution in water.

The composition may be in the form of an emulsion. The emulsion may, forexample, be an oil-in-water emulsion.

The composition may be inserted or mixed into a food substance. Thecomposition may be in the form of a food stuff or a feed. In oneembodiment the food stuff is a human food stuff.

The composition may be in the form of a medical food. The term “medicalfood” as used herein refers to a food product specifically formulatedfor the dietary management of a medical disease or condition; forexample, the medical disease or condition may have distinctivenutritional needs that cannot be met by normal diet alone. The medicalfood may be administered under medical supervision. The medical food maybe for oral ingestion or tube feeding.

The composition may be in the form of a tube feed. The term “tube feed”refers to a product which is intended for introducing nutrients directlyinto the gastrointestinal tract of a subject by a feeding tube. A tubefeed may be administered by, for example, a feeding tube placed throughthe nose of a subject (such as nasogastric, nasoduodenal, andnasojejunal tubes), or a feeding tube placed directly into the abdomenof a subject (such as gastrostomy, gastrojejunostomy, or jejunostomyfeeding tube).

The composition may be in the form of a nutritional composition or anutritional supplement. The term “nutritional supplement” refers to aproduct which is intended to supplement the general diet of a subject.

The composition may be in the form of a complete nutritional product.The term “complete nutritional product” refers to a product which iscapable of being the sole source of nourishment for the subject.

In various embodiments the composition may be in the form of a beverage,mayonnaise, salad dressing, margarine, low fat spread, dairy product,cheese spread, processed cheese, dairy dessert, flavoured milk, cream,fermented milk product, cheese, butter, condensed milk product, icecream mix, soya product, pasteurised liquid egg, bakery product,confectionary product, confectionary bar, chocolate bar, high fat bar,liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding,pasteurised pudding, gel, jelly, yoghurt, or a food with a fat-based orwater-containing filling.

In one embodiment the composition may be an infant formula.

In yet other embodiments the composition of the invention may be used tocoat a food, snack, pet food, or pet treat.

The composition may in the form of a pharmaceutical composition and maycomprise one or more suitable pharmaceutically acceptable carriers,diluents and/or excipients.

Examples of such suitable excipients for compositions described hereinmay be found in the “Handbook of Pharmaceutical Excipients, 2nd Edition,(1994), Edited by A Wade and P J Weller.

Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like. Examplesof suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as, or in addition to, the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s).

Examples of suitable binders include starch, gelatin, natural sugarssuch as glucose, anhydrous lactose, free-flow lactose, beta-lactose,corn sweeteners, natural and synthetic gums, such as acacia, tragacanthor sodium alginate, carboxymethyl cellulose and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like.

Preservatives, stabilizers, dyes and even flavouring agents may beprovided in the composition. Examples of preservatives include sodiumbenzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidantsand suspending agents may be also used.

Nutritionally acceptable carriers, diluents and excipients include thosesuitable for human or animal consumption and that are used as standardin the food industry.

Typical nutritionally acceptable carriers, diluents and excipients willbe familiar to the skilled person in the art.

Administration

The compositions as described herein may be administered enterally orparenterally.

Preferably, the composition is administered enterally. For example, thecomposition may be administered in the form of a food stuff or asupplement.

Enteral administration may be oral, gastric, and/or rectal.

In one embodiment, the composition is administered orally.

In general terms, administration of the composition as described hereinmay, for example, be by an oral route or another route into thegastro-intestinal tract, for example the administration may be by tubefeeding.

The subject may be a mammal such as a human, canine, feline, equine,caprine, bovine, ovine, porcine, cervine and primates. Preferably thesubject is a human.

In one embodiment the subject is an infant. The infant may, for example,be a human such as a newborn infant (i.e. a baby under 28 days of age)or a premature infant (i.e. a baby born before 37 completed weeks ofgestation).

In one embodiment the subject is an aging subject. For instance, asubject may be an aging subject when it has reached 40, 50, 60, 66, 70,75, or 80% of its likely lifespan. A determination of lifespan may bebased on actuarial tables, calculations, or estimates, and may considerpast, present, and future influences or factors that are known topositively or negatively affect lifespan. Consideration of species,gender, size, genetic factors, environmental factors and stressors,present and past health status, past and present nutritional status, andstressors may be taken into consideration when determining lifespan. Theaging subject may, for example, be a human subject over the age of 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 years old.

Treatment

It is to be appreciated that all references herein to treatment includecurative, palliative and prophylactic treatment. Treatment may alsoinclude arresting progression in the severity of a disease.

Both human and veterinary treatments are within the scope of theinvention.

Free fatty acids and ketones produced from MCTs can provide analternative energy source to glucose to supplement or replace the energyin cells such as astrocytes, myocytes, cardiomyocytes, or neuronalcells.

Brain tissue consumes a large amount of energy in proportion to itsvolume. In an average healthy subject, the brain gets most of its energyfrom oxygen-dependent metabolism of glucose. Typically, the majority ofthe brain's energy is used to help neurons or nerve cells send signalsand the remaining energy is used for cell-health maintenance.

A deficiency in brain energy, for example caused by impairment ofglucose utilisation, can result in neuronal hyperactivity, seizures andcognitive impairments.

Examples of brain energy deficiency conditions or diseases include:migraine, memory disorder, age-related memory disorder, brain injury,neurorehabilitation, stroke and post-stroke, amyloid lateral sclerosis,multiple sclerosis, cognitive impairment, cognitive impairmentpost-intensive care, age-induced cognition impairment, Alzheimer'sdisease, Parkinson's disease, Huntingdon's disease, inherited metabolicdisorders (such as glucose transporter type 1 deficiency syndrome andpyruvate dehydrogenase complex deficiency), bipolar disorder,schizophrenia, and/or epilepsy.

As used herein the term “neurological condition” refers to a disorder ofthe nervous system. Neurological conditions may result from damage tothe brain, spinal column or nerves, caused by illness or injury.Examples of the symptoms of a neurological condition include paralysis,muscle weakness, poor coordination, loss of sensation, seizures,confusion, pain and altered levels of consciousness. An assessment ofthe response to touch, pressure, vibration, limb position, heat, cold,and pain as well as reflexes can be carried out to determine whether thenervous system is impaired in a subject.

Some neurological conditions are life-long and the onset can beexperienced at any time. Other neurological conditions, such as cerebralpalsy, are present from birth. Some neurological conditions, such asDuchenne muscular dystrophy, commonly appear in early childhood, otherneurological conditions, such as Alzheimer's disease and Parkinson'sdisease, affect mainly older people. Some neurological conditions have asudden onset due to injury or illness, such as a head injury or stroke,or cancers of the brain and spine.

In one embodiment, the neurological condition is the result of traumaticdamage to the brain.

In addition, or alternatively, the neurological condition is the resultof an energy deficiency in the brain or in the muscles.

Examples of neurological conditions include migraine, memory disorder,age-related memory disorder, brain injury, neurorehabilitation, strokeand post-stroke, amyloid lateral sclerosis, multiple sclerosis,cognitive impairment, cognitive impairment post-intensive care,age-induced cognition impairment, Alzheimer's disease, Parkinson'sdisease, Huntingdon's disease, inherited metabolic disorders (such asglucose transporter type 1 deficiency syndrome and pyruvatedehydrogenase complex deficiency), bipolar disorder, schizophrenia,and/or epilepsy.

A migraine is an intense headache accompanied by other symptoms such asnausea (feeling sick), visual problems and an increased sensitivity tolight or sound. A migraine may be preceded by an aura; the main symptomsof an aura are visual problems such as blurred vision (difficultyfocussing), blind spots, flashes of light, or a zigzag pattern movingfrom the central field of vision towards the edge.

Strokes (also known as cerebrovascular accident (CVA) andcerebrovascular insult (CVI)) occur when there is poor blood flow to thebrain resulting in cell death. There are two main types of stroke:ischemic, due to lack of blood flow, and haemorrhagic due to bleeding.Strokes result in part of the brain not functioning properly. The signsand symptoms of a stroke may include an inability to move or feel on oneside of the body, problems understanding or speaking, feeling like theworld is spinning, or loss of vision to one side. The signs and symptomsoften appear soon after the stroke has occurred.

Amyotrophic lateral sclerosis (ALS) (also known as Lou Gehrig's disease,Charcot disease and motor neurone disease), involves the death ofneurons responsible for controlling voluntary muscles. ALS ischaracterized by stiff muscles, muscle twitching, and graduallyworsening weakness due to muscle wasting; this results in difficultyspeaking, swallowing, and eventually breathing.

Multiple sclerosis affects the nerves in the brain and spinal cord,causing a wide range of symptoms including problems with musclemovement, problems with mobility and balance, numbness and tingling,blurring of vision (typically there is loss of vision in one eye) andfatigue.

Parkinson's disease is a degenerative disorder of the central nervoussystem mainly affecting the motor system. In the early course of thedisease, the most obvious symptoms are movement-related; these includetremor at rest, rigidity, slowness of movement and difficulty withwalking and gait. Later on in the course of the disease thinking andbehavioural problems may arise, with dementia commonly occurring in theadvanced stages of the disease. Other symptoms include depression,sensory, sleep and emotional problems.

Alzheimer's disease is a progressive neurodegenerative disorder.Alzheimer's disease is the most common cause of dementia. Symptomsinclude memory loss and difficulties with thinking, problem-solving orlanguage. The mini mental state examination (MMSE) is an example of oneof the tests used to diagnose Alzheimer's disease.

Huntington's disease is an inherited condition that damages certainnerve cells in the brain. Huntington's disease affects musclecoordination and leads to mental decline and behavioural symptoms. Theearliest symptoms are often subtle problems with mood or cognition. Ageneral lack of coordination and an unsteady gait often follow. As thedisease advances, uncoordinated, jerky body movements become moreapparent, along with a decline in mental abilities and behaviouralsymptoms. Physical abilities gradually worsen until coordinated movementbecomes difficult. Mental abilities generally decline into dementia.

Inherited metabolic disorders are a range of diseases caused bydefective genes. Typically the defective gene(s) results in a defect inan enzyme or in a transport protein which results in a block in the waythat a compound is processed by the body such that there is a toxicaccumulation of the compound. Inherited metabolic disorders can affectany organ and usually affect more than one. Symptoms often tend to benon-specific and usually relate to major organ dysfunction or failure.The onset and severity of a metabolic disorder may be exacerbated byenvironmental factors, such as diet and concurrent illness.

Glucose transporter type 1 (Glut1) deficiency syndrome is a geneticmetabolic disorder involving the GLUT1 protein which transports glucoseacross the blood-brain barrier or the boundary separating tiny bloodvessels from brain tissue. The most common symptom is seizures(epilepsy), which usually begin within the first few months of life.Additional symptoms that can occur include varying degrees of cognitiveimpairment and movement disorders characterized by ataxia, dystonia, andchorea. Glut1 deficiency syndrome may be caused by mutations in theSLC2A1 gene which produce GLUT1 protein.

Pyruvate dehydrogenase complex deficiency (pyruvate dehydrogenasedeficiency or PDCD) is a neurodegenerative disorder associated withabnormal mitochondrial metabolism and disrupted carbohydrate metabolism.PDCD is characterized by the buildup of lactic acid in the body and avariety of neurological problems. Signs and symptoms of this conditionusually first appear shortly after birth, and they can vary widely amongaffected individuals. The most common feature is a potentiallylife-threatening buildup of lactic acid (lactic acidosis), which cancause nausea, vomiting, severe breathing problems, and an abnormalheartbeat. Other symptoms include: neurological problems; delayeddevelopment of mental abilities and motor skills such as sitting andwalking; intellectual disability; seizures; weak muscle tone(hypotonia); poor coordination, and difficulty walking. Some affectedindividuals have abnormal brain structures, such as underdevelopment ofthe tissue connecting the left and right halves of the brain (corpuscallosum), wasting away (atrophy) of the exterior part of the brainknown as the cerebral cortex, or patches of damaged tissue (lesions) onsome parts of the brain. PDCD is a deficiency of one of the proteins inthe pyruvate dehydrogenase complex (PDC). The pyruvate dehydrogenasecomplex comprises three enzymes identified as E1, E2, and E3; the E1enzyme contains subunits identified as alpha and beta. The most commonform of PDCD is caused by an abnormal gene in the E1 alpha subunit (thePDHA1 gene) located on the X chromosome. Some PDCD cases are caused by amutation in a gene in another subunit of the pyruvate dehydrogenasecomplex such as the PDHX gene, the PDHB gene, the DLAT gene, the PDP1gene, and the DLD gene.

Bipolar disorder is a brain disorder that causes unusual shifts in mood,energy, activity levels, and the ability to carry out day-to-day tasks.Bipolar disorder is characterized by periods of elevated mood andperiods of depression. Bipolar disorder can be diagnosed using theguidelines from the Diagnostic and Statistical Manual of MentalDisorders (DSM) or the World Health Organization's InternationalStatistical Classification of Diseases and Related Health Problems.

Schizophrenia is a chronic, severe, and disabling brain disorder inwhich individuals interpret reality abnormally. Schizophrenia may resultin some combination of hallucinations, hearing voices, delusions, andextremely disordered thinking and behavior. Schizophrenia can bediagnosed using the guidelines from the Diagnostic and StatisticalManual of Mental Disorders (DSM) or the World Health Organization'sInternational Statistical Classification of Diseases and Related HealthProblems.

Epilepsy is a neurological disorder in which nerve cell activity in thebrain becomes disrupted, causing seizures or periods of unusualbehaviour, sensations and sometimes loss of consciousness.

The terms “cognitive impairment” and “cognition impairment” refer todisorders that give rise to impaired cognition, in particular disordersthat primarily affect learning, memory, perception, and/or problemsolving.

Cognitive impairment may occur in a subject after intensive care.Cognitive impairment may occur as part of the ageing process.

The term “cognition” refers to the set of all mental abilities andprocesses, including knowledge, attention, memory and working memory,judgment and evaluation, reasoning and “computation”, problem solvingand decision making, comprehension and production of language.

Levels of and improvements in cognition can be readily assessed by theskilled person using any suitable neurological and cognitive tests thatare known in the art, including cognitive tests designed to assess speedof information processing, executive function and memory. Suitableexample tests include Mini Mental State Examination (MMSE), CambridgeNeuropsychological Test Automated Battery (CANTAB), Alzheimer's DiseaseAssessment Scale-cognitive test (ADAScog), Wisconsin Card Sorting Test,Verbal and Figural Fluency Test and Trail Making Test, Wechsler Memoryscale (WMS), immediate and delayed Visual Reproduction Test (Trahan etal. Neuropsychology, 1988 19(3) p. 173-89), the Rey Auditory VerbalLearning Test (RAVLT) (Ivnik, R J. et al. Psychological Assessment: AJournal of Consulting and Clinical Psychology, 1990 (2): p. 304-312),electroencephalography (EEG), magnetoencephalography (MEG), PositronEmission Tomography (PET), Single Photon Emission Computed Tomography(SPECT), Magnetic Resonance Imaging (MRI), functional Magnetic ResonanceImaging (fMRI), computerised tomography and long-term potentiation.

EEG, a measure of electrical activity of the brain, is accomplished byplacing electrodes on the scalp at various landmarks and recordinggreatly amplified brain signals. MEG is similar to EEG in that itmeasures the magnetic fields that are linked to electrical fields. MEGis used to measure spontaneous brain activity, including synchronouswaves in the nervous system.

PET provides a measure of oxygen utilisation and glucose metabolism. Inthis technique, a radioactive positron-emitting tracer is administered,and tracer uptake by the brain is correlated with brain activity. Thesetracers emit gamma rays which are detected by sensors surrounding thehead, resulting in a 3D map of brain activation. As soon as the traceris taken up by the brain, the detected radioactivity occurs as afunction of regional cerebral blood flow. During activation, an increasein cerebral blood flow and neuronal glucose metabolism can be detectedwithin seconds.

Suitable analysis can also be based on neuropsychiatric testing,clinical examinations and individual complaints of loss of cognitivefunction (e.g. subjective memory loss).

Further suitable tests may be based on assessments of locomotion, memoryand attention, seizure susceptibility, and social interaction and/orrecognition.

Memory disorders are the result of neurological damage to the brainstructures such that the storage, retention and recollection of memoriesis hindered. Memory disorders can be progressive with age (e.g.Alzheimer's disease), or they can be immediate resulting, for example,from a head injury. Levels of and improvements in memory disorders canbe readily assessed by the skilled person using any suitable tests thatare known in the art such as Alzheimer's Disease AssessmentScale-cognitive test (ADAScog), Mini Mental State Examination (MMSE),computerised tomography (CT) scan, Magnetic Resonance Imaging (MRI),Single Photon Emission Computed Tomography (SPECT), Positron EmissionTomography (PET), and electroencephalography (EEG).

As used herein, the term “treatment” means to administer a compositionas described herein to a subject having a condition in order to lessen,reduce or improve at least one symptom associated with the conditionand/or to slow down, reduce or block the progression of the condition.

To “prevent” means to administer a composition as described herein to asubject is not showing any symptoms of the condition to reduce orprevent development of at least one symptom associated with thecondition.

Ketones

After oral absorption, MCT are metabolised to free fatty acids andfurther metabolised to ketones. The free fatty acids are initiallymetabolised to β-hydroxy butyrate (BHB) and then aceto acetate (AcA).

MCFA and ketones can be produced in various amounts in bodily fluidsdepending on the MCT utilized, and they may be used as an alternativesource of energy to glucose or to supplement the energy derived fromglucose.

Ketones can be transported to the brain by, for example, monocarboxylictransporter 1 (MCT1) where they are mainly metabolised by neurones. Freefatty acids, such as C8 free fatty acids and C10 free fatty acids, canreach the brain by diffusion where they are mainly metabolised byastrocytes (see FIG. 1).

In one embodiment, the composition according to the present invention isfor use in providing ketones and/or C10 fatty acids to a bodily fluid ofa subject.

Preferably, the ketones are β-hydroxy butyrate and/or aceto acetate.

In one embodiment the exposure of the subject to ketones and/or C10fatty acids following oral administration of the composition of thepresent invention is greater than following oral administration of acomposition comprising the MCT species shown in Table 1:

TABLE 1 Species in MCT(mixC8/C10 60:40) Mole % MCT-C8 22% MCT-C10 10%MCT(mix C8/C10) 2:1 34% MCT(mix C8/C10) 1:2 34%

In one embodiment the exposure of the subject to ketones and/or C10fatty acids following oral administration of the composition accordingto the present invention is at least 1, 2, 3, 4, 5, 6, 7 or 8 mol %greater than following oral administration of a composition comprisingthe MCT species shown in Table 1.

In one embodiment the exposure of the subject to ketones and/or C10fatty acids is quantified by measuring the levels of ketones and/or C10fatty acids in the subject's plasma.

In one embodiment the exposure of the subject to ketones and/or C10fatty acids is measured over 8 hours following oral administration

The exposure of a subject to a ketone and/or C10 fatty acid may becalculated by determining the area under the curve (AUC) in a plot ofconcentration of ketone and/or C10 fatty acid in a bodily fluid e.g.,blood plasma, against time (e.g. over 8 or 24 hours). Prior to analysis,biological fluids are either treated with organic solvent to precipitateprotein and reconstituted in a mass spectrometry (MS) compatiblesolvent. Levels of ketone bodies and medium chain fatty acids areassessed using liquid chromatography coupled to high resolution massspectrometry (LC-MS). In particular, β-hydroxy butyrate (BHB), acetoacetate (AcA), C8 fatty acids and C10 fatty acid concentrations arequantitatively measured using an external calibration methodology.

Various preferred features and embodiments of the present invention willnow be described by way of non-limiting examples.

EXAMPLES

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA and immunology, which are within thecapabilities of a person of ordinary skill in the art. Such techniquesare explained in the literature. See, for example, J. Sambrook, E. F.Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual,Second Edition, Books 1-3, Cold Spring Harbor Laboratory Press; Ausubel,F. M. et al. (1995 and periodic supplements; Current Protocols inMolecular Biology, ch. 9, 13, and 16, John Wiley & Sons, New York,N.Y.); B. Roe, J. Crabtree, and A. Kahn, 1996, DNA Isolation andSequencing: Essential Techniques, John Wiley & Sons; J. M. Polak andJames O'D. McGee, 1990, In Situ Hybridization: Principles and Practice;Oxford University Press; M. J. Gait (Editor), 1984, OligonucleotideSynthesis: A Practical Approach, Irl Press; D. M. J. Lilley and J. E.Dahlberg, 1992, Methods of Enzymology: DNA Structure Part A: Synthesisand Physical Analysis of DNA Methods in Enzymology, Academic Press; andE. M. Shevach and W. Strober, 1992 and periodic supplements, CurrentProtocols in Immunology, John Wiley & Sons, New York, N.Y. Each of thesegeneral texts is herein incorporated by reference.

Example 1—a Blend of MCT-C8 and MCT-C10 Provides More C10 FFA andKetones than a MCT(C8/C10 MIX)

Materials and Methods

TABLE 2 MCT-C8 MCT-C10 MCT (C8/10 MIX) R1 R2 R3 R1 R2 R3 R1 R2 R3 C₇H₁₅C₇H₁₅ C₇H₁₅ C₇H₁₅ C₇H₁₅ C₇H₁₅ C₇H₁₅ C₇H₁₅ C₉H₁₇ C₇H₁₅ C₉H₁₇ C₇H₁₅ C₉H₁₇C₇H₁₅ C₇H₁₅ C₇H₁₅ C₉H₁₇ C₉H₁₇ C₉H₁₇ C₇H₁₅ C₉H₁₇ C₉H₁₇ C₉H₁₇ C₇H₁₅ C₉H₁₇C₉H₁₇ C₉H₁₇ C₉H₁₇ C₉H₁₇ C₉H₁₇ One molecular species One molecularspecies 8 molecular species

The MCT oil “PLUS” as used herein comprises (i) a homotriglyceridemedium-chain triglyceride (MCT) comprising three fatty acid moietieseach with 8 carbon atoms (MCT-C8) and (ii) a homotriglyceride MCTcomprising three fatty acid moieties each with 10 carbon atoms(MCT-C10); wherein the ratio of MCT-C8 to MCT-C10 is about 60:40(mol/mol).

Typically MCT oils are mixtures of triglycerides and homotriglycerides.The right-hand column of Table 2 details one such mixture. These oilswere synthesised by esterification of glycerol with a mixture of C8 andC10 acid with a given ratio.

Mass Spectrum analysis of one MCT-mix (C8/C10 60:40) (the oil used toprepare Peptamen®) revealed that pure MCT-C8 (homotriglyceride) andMCT-C10 (homotriglyceride) amount to 32% only, the remaining 68%included a mixed backbone with C8:C10 ratio of 2:1 or 1:2, as shownbelow:

Species in MCT(mixC8/C10 60:40) Mole % MCT-C8 22% MCT-C10 10% MCT(mixC8/C10) 2:1 34% MCT(mix C8/C10) 1:2 34%

The MCT oil mixture “MCT (C8/C10 MIX)” as used herein comprises (i)MCT-C8, (ii) MCT-C10, (iii) MCT(mix C8/C10 2:1) and (iv) MCT(mix C8/C101:2). The terms “MCT (C8/C10 MIX)” and “MCT(C8/C10 MIX 60:40)” and “MIX”may be interchangeable.

The biodisposition and metabolism of the 8 molecular species in theMCT-mix (C8/C10 MIX 60:40) vary. Hence the overall properties of theMCT(C8/C10 MIX) are the observed average of the 8 species. Moreover, theamount of these 8 species cannot be controlled during the synthetic stepand are not fully characterized (see above Table 2).

Rats were orally fed a mixture of MCT-C8 plus MCT-C10 (herein referredto as PLUS) at a 60:40 ratio or a MCT(C8/C10 MIX) oil (herein referredto as MIX). Oral administrations of compound preparations were performedon unanaesthetized freely moving animals using an oral gavage probe.MCT-C8 oil and MIX oil were administered at room-temperature. MCT-C10oil and PLUS oil were heated until solutions were obtained (atapproximately 50° C.) and were administered at approximately 30° C. tothe animals.

Blood samples were collected through the catheters implanted on theprevious day. For each time point, a sufficient volume of blood wascollected and transferred in K3-EDTA tubes in order to get at least 140microliters of plasma after centrifugation. After each blood sampling,the same volume of saline was administrated to the animal through thecatheter both with a small volume of saline containing heparin.

After centrifugation (10 min at 3500 rpm and at 4° C.) and for eachblood sample, the volume of plasma collected was split into two aliquotsof roughly equal volume (70 μl) and stored at around −60° C. until LC-MSanalysis of free fatty acids and ketones (see above).

Results and Discussion

The present inventor found that at the same C8/C10 ratio, a blend ofMCT-C8 plus MCT-C10 (PLUS) is superior to MCT(mixC8/10) in providingmore plasma C10 free fatty acids when administered to mammals. At thesame time, the level of ketone increases by 8%.

Various distinct biological activities have been linked to each C8 fattyacid, C10 fatty acid and ketone species. Hence the ability to modulatethe exposure of a subject or tissue of a subject to C8 free fatty acids,C10 free fatty acids and ketones enables the modulation of their overallbiological activities.

Surprisingly, the present inventor found that in orally fed rats amixture of MCT-C8 plus MCT-C10 (herein referred to as PLUS) at a 60:40ratio provides larger plasma C10 free fatty acids than a MCT(C8/C10 MIX)oil (MIX) with the same C8/C10 60:40 ratio. The total MCFA AUC (C8 FFAand C10 FFA) remains the same in PLUS and in MIX. See FIG. 2.

At the same time, the ketone level of PLUS as determined by AUC over thefirst 8 hours is greater by about 8% compared to the ketone produced byMIX (Table 3).

TABLE 3 plasma ketone exposure over 8 hours AUC (microM/h) Plus 11365Mix 10484

TABLE 4 Plasma C8 FFA and C10 FFA exposure over 24 hours AUC (microM/h)AUC % C8 C10 C8 C10 PLUS 0-24 216 304 41.6 58.4 MIX 0-24 315 214 58.640.4 p 0.023 0.092

All publications mentioned in the above specification are hereinincorporated by reference. Various modifications and variations of thedescribed compositions or uses of the present invention will be apparentto those skilled in the art without departing from the scope and spiritof the present invention. Although the present invention has beendescribed in connection with specific preferred embodiments, it shouldbe understood that the invention as claimed should not be unduly limitedto such specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention, which are obvious tothose skilled in biochemistry and biotechnology or related fields, areintended to be within the scope of the following claims.

The invention claimed is:
 1. A method for providing ketones and/or C10fatty acids to a subject in need thereof, the method comprisingadministering to the subject a composition comprising medium-chaintriglycerides (MCTs) comprising a MCT comprising three fatty acidmoieties each with 8 carbon atoms (MCT-C8) and a MCT comprising threefatty acid moieties each with 10 carbon atoms (MCT-C10), wherein a ratioof the MCT-C8 to the MCT-C10 is from 10:90 to 90:10 (mol/mol), andwherein the combined amount of the MCT-C8 and the MCT-C10 is at least 50mol % of the MCTs in the composition, wherein the composition providesincreased ketones and/or fatty acids as compared to a compositioncomprising MCTs comprising three fatty acids moieties each with a mix ofC8 and C10 moieties attached and having the same C8/C10 ratio and molaramounts.
 2. The method according to claim 1, wherein the ketonescomprise at least one of β-hydroxy butyrate or aceto acetate.
 3. Themethod according to claim 1 wherein exposure of the subject to theketones following the administering of the composition is greater thanfollowing an administration of a composition comprising the followingMCT species: Species in MCT(mixC8/C10 60:40) Mole % MCT-C8 22% MCT-C1010% MCT(mix C8/C10) 2:1 34% MCT(mix C8/C10) 1:2 34%

wherein mixC8/10 2:1 is a MCT comprising two fatty acid moieties having8 carbon atoms and one fatty acid moiety having 10 carbon atoms, andwherein mixC8/10 1:2 is a MCT comprising one fatty acid moiety having 8carbon atoms and two fatty acid moieties having 10 carbon atoms.
 4. Themethod according to claim 1, wherein the individual has a disorderselected from the group consisting of a brain energy deficiencycondition, a neurological condition, migraine, memory disorder,age-related memory disorder, brain injury, stroke, amyloid lateralsclerosis, multiple sclerosis, cognitive impairment, cognitiveimpairment post-intensive care, age-induced cognition impairment,Alzheimer's disease, Parkinson's disease, Huntingdon's disease,inherited metabolic disorders, bipolar disorder, schizophrenia,epilepsy, and combinations thereof.
 5. The method according to claim 1,wherein the composition is administered enterally.
 6. The methodaccording to claim 1, wherein the composition is in the form of a foodstuff or a feed.
 7. The method according to claim 1, wherein thecomposition is in a form selected from the group consisting of a medicalfood, a tube feed, a nutritional composition and a nutritionalsupplement.
 8. The method according to claim 1, wherein the compositionis in a form selected from the group consisting of a beverage,mayonnaise, salad dressing, margarine, low fat spread, dairy product,cheese spread, processed cheese, dairy dessert, flavoured milk, cream,fermented milk product, cheese, butter, condensed milk product, icecream mix, soya product, pasteurised liquid egg, bakery product,confectionary product, confectionary bar, chocolate bar, high fat bar,liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding,pasteurised pudding, gel, jelly, yoghurt, and a food with a fat-based orwater-containing filling.
 9. The method according to claim 1, whereinthe ratio of the MCT-C8 to the MCT-C10 is from 20:80 to 85:15 (mol/mol).10. The method according to claim 1, wherein the ratio of the MCT-C8 tothe MCT-C10 is from 50:50 to 67:33 (mol/mol).
 11. The method accordingto claim 1, wherein the ratio of the MCT-C8 to the MCT-C10 is from 55:45to 65:35 (mol/mol).
 12. The method according to claim 1, wherein theratio of the MCT-C8 to the MCT-C10 is from 58:42 to 62:38 (mol/mol). 13.The method according to claim 1, wherein the ratio of the MCT-C8 to theMCT-C10 is about 60:40 (mol/mol).
 14. The method according to claim 1,wherein the combined amount of the MCT-C8 and the MCT-C10 is at least 90mol % of the MCTs in the composition.
 15. The method according to claim1, wherein the three fatty acid moieties each with 8 carbon atoms areoctanoic acid moieties, and/or the three fatty acid moieties each with10 carbon atoms are decanoic acid moieties.
 16. The method according toclaim 1, wherein the subject has a brain energy deficiency condition.17. The method according to claim 1, wherein the composition furthercomprises an agent that promotes or sustains neurologic health orenhance cognitive function, and the agent is selected from the groupconsisting of vitamins, choline, phosphatidylserine, alpha-lipoic acid,CoQ10, acetyl-L-carintine, herbal extracts, omega-3 or omega-6polyunsaturated fatty acids, aliphatic ester, fish oil extracts, andcombinations thereof.